Coronary heart disease (CHD) remains the most important cause of mortality. Myocardial infarction and unstable angina result from formation of a platelet thrombus, a process that requires the binding of extracellular adhesive ligands to the GPIIb-IIIa receptor on the surface of platelets. Percutaneous transluminal coronary angioplasty (PTCA/stenting) also results in disruption of vessel integrity at the location of an atherosclerotic plaque and during and after these procedures (up to thirty days, currently), there is an absolute requirement for antithrombotic therapy. The GPIlb-IIIa receptor is known to be polymorphic and the presence of the PLA2 allele has been associated with an increased prevalence of ischemic syndromes, especially in younger individuals. Recently, the PLA2 polymorphism has emerged as an important risk for sudden coronary death in patients less than 60 with myocardial infarction and adverse events in patients undergoing coronary stenting. Numerous studies have reported varying results with regard to this novel risk factor. It is fair to say that, as a result of divergent results generated by these subsequent studies, two camps have emerged: those who believe that PLA2 is a risk factor for arterial thrombosis, and those who do not. Our ability to interpretepidemiological data is limited by the lack of understanding of the effect of the PLA2 polymorphism on platelet biology and thrombosis. We have previously demonstrated that a differential effect of aspirin (ASA) on platelet aggregation occurs in platelets that demonstrate the PLA2 polymorphism, which may in part, explain the divergent results of PLA and CHD in numerous studies. We have conducted a study to characterize the impact of PLA2 on platelet response to agonists, in patients with CHD, randomized to receive ASA, (325mg/day), clopidogrel (75mg/day) or a combination of ASA and clopidogrel. We have shown that PLA functions as an important modifier for the platelet response to ASA, clopidogrel or their combination in CHD patients. ASA+clopidogrel appears superior than ASA alone in reducing platelet aggregation. Our data suggest that responses to clopidogrel and ASA, both, are PLA sensitive. The synergy between ASA and clopidogrel in PLA 1/A2 patients is interesting and could involve ASA inhibition of COX-1. However, when administered at 325mg per day, a contribution of COX-2 inhibition to this synergistic effect is possible. The overall hypothesis of this proposal is that genetics, and specifically the PLA2 polymorphism, can be used to determine optimum antiplatelet therapy in patients with CHD. This will be tested in patients with CHD, post-stent, by randomizing them to receive either ASA, clopidogrel, or ASA and clopidogrel and assessing clinical and platelet functional endpoints as a function of PLA. In addition, to expand our understanding to novel mechanisms of antiplatelet therapy we will also assess the potential benefit of COX-2 inhibition with a specific COX-2 inhibitor, rofecoxib. Such information will be paramount in the targeting of antiplatelet therapies and will be based on genomlc information (pharmacogenetics).